Process for the production of carboxamides of oxo-1,2-benzothiazine-1,1-dioxides

ABSTRACT

Disclosed herein is an improved process for the production of carboxamides of 3,4-dihydro-oxo-1,2-benzothiazine-1,1-dioxides. Said process comprises contacting either a 4-alkoxy-1,2benzothiazine-3-carboxylic acid-1,1-dioxide or a 3-alkoxy-1,2benzothiazine-4-carboxylic acid-1,1-dioxide with an amine followed by cleavage of the ether moiety with an appropriate reagent such as hydrogen bromide to produce a carboxanilide with previously disclosed pharmaceutical value as a non-steroidal anti inflammatory agent. The alkoxy-benzothiazine carboxylic acids are themselves novel compounds and valuable synthetic intermediates.

United States Patent [1 1 Lombardino PROCESS FOR THE PRODUCTION OFCARBOXAMIDES OF OXO- 1 ,Z-BENZOTHIAZINE- 1 l -DIOXIDES [75] Inventor:Joseph G. Lombardino, Niantic,

Conn. [73] Assignee: Pfizer Incl, New York, NY.

[22] Filed: Oct. 15, 1974 [21] Appl. No.: 514,570

[111 3,892,740 [451 July 1, 1975 Primary Examiner-John M. Ford Attorney,Agent, or Firm-Connolly and Hutz [5 7] ABSTRACT Disclosed herein is animproved process for the production of carboxamides of3,4-dihydro-oxo-l,2- benzothiazine-l,l-dioxides. Said process comprisescontacting either a 4-alkoxy-1,2-benzothiazine-3- carboxylicacid-l,l-dioxide or a 3-alkoxy-l,2- benzothiazine-4-carboxylicacid-1,1-dioxide with an amine followed by cleavage of the ether moietywith an appropriate reagent such as hydrogen bromide to produce acarboxanilide with previously disclosed pharmaceutical value as anon-steroidal anti inflammatory agent. The alkoxy-benzothiazinecarboxylic acids are themselves novel compounds and valuable syntheticintermediates.

12 Claims, N0 Drawings PROCESS FOR THE PRODUCTION OF CARBOXAMIDES OFOXO-l,Z-BENZOTHIAZINE-l,l-DIOXIDES CROSS REFERENCE TO RELATED PATENTSThe products of the process of the instant invention are claimed in mycommonly assigned US. Pat. No. 3,591,584, issued July 6, 1971, thedisclosure of which is incorporated herein by reference.

BACKGROUND OF THE INVENTION wherein X, Y and R, are as defined hereinbelow, with an organic isocyanate of the formula R'NCO wherein R isselected from the group consisting of hydrogen, alkyl having one toeight carbon atoms, phenylalkyl having up to three carbon atoms in thealkyl moiety, phenyl, substituted phenyl and naphthyl to produce acompound of the general structuralformula ll C-NHR or S R1 2 Y 02 IIIThe second method was employed in the preparation of those compoundswherein the N-substituent is a heterocyclic moiety such as substitutedor unsubstituted pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,pyrazolonyl,

thiazolyl, isothiazolyl, benzothiazolyl, benzoxazolyl or thiadiazolyl.The isocyanate route was not used to prepare these compounds because therequisite heterocyclic isocyanates are either unstable or extremelydifficult to synthesize. The 4-carboxamides were prepared from compoundsof Formula lV wherein R is a mono-,

dior unsubstituted phenyl and the substituents are chosen from the groupconsisting of fluorine, chlorine, bromine, nitro, trifluoromethyl andalkyl and alkoxy having from one to three carbon atoms. Said compoundswere contacted with an alcohol to form the corresponding 3- or4-carboxylic acid ester by the alcoholysis method well-known to thoseskilled in the art. The 3-carboxamides were prepared from knowncompounds such as a 3-oxo-l,Z-benzothiazoIine-Z-acetic acid ester,[Chemische Berichte, Vol. 30, p. 1267 (1897).]. Said benzothiazolineswere treated with an alkali metal alkoxide like sodium methoxide in apolar solvent such as dimethylsulfoxide or dimethylformamide wherebythey rearrange to the corresponding 3,-4-dihydro-4-oxo-2H-1,Z-benzothiazine-3-carboxylate- 1,1-dioxide ester.[Journal of Organic Chemistry, Vol. 30 p. 2241 (1965).]. This compoundis then treated with an alkyl halide, preferably an iodide, wherein thealkyl group is identical with R to yield the desired ester. Said 3- and4- esters were then contacted with at least an equimolar amount of anamine of the general formula R"NH wherein R" is one of the heterocyclicmoieties of interest to produce the desired benzothiazine carboxamidewhich is N-substituted with a heterocyclic moiety. Standard ammonolysisprocedures known to those skilled in the art of organic chemistry wereemployed.

SUMMARY OF THE INVENTION The process of this invention is for theproduction of a 3,4-dihydro-2I-l-l ,2-benzothiazine-carboxamidel ldioxide of the formula wherein X and Y are each selected from the groupconsisting hydrogen, fluorine, chlorine, bromine, nitro, trifluoromethyland alkyl and alkoxy each having from one to five carbon atoms; R is amember selected from the group consisting of hydrogen, alkyl having upto six carbon atoms, alkenyl having up to four carbon atoms, andphenylalkyl having up to three carbon atoms in the alkyl moiety;

and R is amember selected from the group consisting of hydrogen, alkylhaving from one to eight carbon atoms, alkenyl having up to six carbonatoms, cycloalkyl having up to eight carbon atoms, phenylalkyl having upto three carbon atoms in the alkyl moiety, phenyl, nitrophenyl,naphthyl, 2-pyridyl, 3-methyl-2- pyridyl, 4-methyl-2-pyridy1,5-methyl-2-pyridyl, 6-methyl-2-pyridyl, 4,6-dimethyl-2-pyridyl,5-chloro-2- pyridyl, 5-bromo-2-pyridy1, S-nitro-Z-pyridyl,5-carboxamido-2-pyridyl, Z-pyrazinyl, 2-pyrimidyl,4,5-dimethyl-2-pyrimidyl, 4-pyrimidyl, 5-methyl-3- pyrazinyl,6-methoxy-3-pyridazinyl, l-phenyl-3- pyrazolonyl, Z-thiazolyl,4-methyl-2-thiazolyl, 4-phenyl-2-thiazolyl, 5-bromo-2-thiazolyl,4,5-dimethyl-2- thiazolyl, 3-isothiazolyl, 2-benzothiazolyl, 6-methyl-2-benzothiazolyl, 4-chloro-2-benzothiazolyl, 6-bromo-2- benzothiazolyl,5-chloro-2-benzoxazolyl, 1,3 ,4- thiadiazolyl,S-methyl-l,2,4-thiadiazolyl, S-methyl- 1,3,4-thiadiazolyl,1,2,4-triazolyl and 6-phenyl-l,2,4- triazolyl, 7-indazolyl, and monoanddisubstituted phenyl wherein each substituent is selected from the groupconsisting of halogen, hydroxy, alkoxy and thioalkoxy having up to threecarbon atoms, alkyl having up'to four carbon atoms, trifluoromethyl,acetyl, methylsulfinyl and methylsulfonyl.

Said process comprises contacting a compound of the structure VII VIIIwherein R is selected from the group consisting of lower alkyl andphenylalkyl having up to three carbon atoms in the alkyl moiety,

with a substantially equimolar portion of an amine of the formula R NHin reaction-inert solvent such as substantially anhydroustetrahydrofuran or dioxane in the presence of a molar excess of asuitable coupling promoter such as N-ethoxycarbonyl-2-ethoxy-l,2dihydroquinoline, POCI dicyclohexylcarbodiimide orN,N'-carbonyl-diimidazole until the reaction to form the correspondingcarboxamide is substantially complete. Said carboxamide is thencontacted with hydrobromic acid in a reaction-inert solvent such asacetic acid at a temperature between about 50 and 90C. until thereaction to form the corresponding oxocarboxamide of Formula V or VI issubstantially complete.

Preferred products of the process of the instant invention are the3-carboxamides, those in which R, is methyl, those in which X and Y areeach hydrogen and those in which R is Z-thiazolyl or 2-pyridyl.Especially preferred as products are N-(2-thiazolyl)- and N-(2- pyridyl)-3,4-dihydro-2-methyl-4-oxo-2H-l ,2- benzothiazine-3-carboxamidel l-dioxide.

The alkoxybenzothiazine carboxylic acids of Formulas VII and VIII arethemselves novel and valuable synthetic intermediates. They may beprepared in a large number of ways, for instance from the knowncorresponding oxobenzothiazine carboxylic acid esters or methyl ketones.The esters are hydrolyzed to the acid by a variety of methods known tothose skilled in the art. The methyl ketones are oxidized to the acidusing, for example, iodine in pyridine.

The preferred starting materials are those of Formula VII and those inwhich R, is a secondary or tertiary alkyl especially Z-propyl and thepreferred coupling promoter is dihydroquinoline.

DETAILED DESCRIPTION OF THE INVENTION It is known to those skilled inthe art that compounds of the structure shown in Formulas I through VIexist as mixtures of keto and enol tautomers. These formulasN-ethoxycarbonyl-2-ethoxyl ,2-

show the keto tautomers; the enol tautomers have structures of the typewhich differ from the keto tautomers only in the shift of a hydrogenatom and a double bond. Compounds of Formulas VII and VIII do nottautomerize because the R moiety will not shift as the hydrogen atomdoes.

The products of the process of the present invention would be relativelyeasy to prepare if one had available various 3 ,4-dihydro-4-oxo-2H-l,2-benzothiazine-3- carboxylic acid-1,1-dioxides and 3,4-dihydro-3-oxo-2H-l ,2-benzothiazine-4-carboxylic acid-1,1-dioxides. These compoundshave been prepared by hydrolysis of the corresponding ester but theydecarboxylate rapidly once formed. Decarboxylations of this type aredependent on the existence of a B-keto function. They do not occur inthe absence of said functionality and, therefore, compounds of FormulasVII and VII are stable carboxylic acids. Said acids may then becontacted with amines to yield carboxamides and the ether moiety cleavedwith hydrobromic acid to produce the desired anti-inflammatory agents.

The novel intermediates of the present invention are prepared from knowncompounds [l-I. Zinnes et al., Journal of Organic Chemistry, Vol. 30, p.2241 (1965).] of the structure wherein X. Y, R and R are as previouslydefined by contacting them with a substantially equimolar portion ofiodine both dissolved in dry pyridine at a concentration of about 1 to20% by weight at steam bath temperatures until the oxidation reaction issubstantially complete. The mixture is then concentrated in vacuo to aviscous oil, presumably the pyridinium salt. Said salt is then dissolvedat a concentration of about 0.5 to 10% in approximately a ten-fold molarexcess of strong aqueous base such as concentrated potassium hydroxideand the resulting solution heated at steam bath temperatures for about0.5 to 2 hours. The reaction mixture is'then cooled, acidified with astrong mineral acid such as hydrochloric acid and extracted with awaterimmiscible organic solvent such as diethylether or a petroleurnether. Saidorganic extract is itself extracted with a sodium bicarbonatesolution which is then treated with charcoal, filtered and acidifiedwith a strong mineral acid. This aqueous acidic extract is then itselfextracted with one of said water-immiscible organic solvents and theorganic extract is treated with a suitable desiccant and concentrated invacuo to an oil which slowly crystallizes to yield the desiredcarboxylic acid.

The preparation of compounds of the structure 0 X X I 0-OR u 11 C-OP Oand N R g 1 1 Y 2 Y 2 XI XII wherein R, is selected from the groupconsisting of alkyl having up to 12 carbon atoms, benzyl, phenylethyland phenylpropyl and X, Y and R are as defined above is disclosed in US.Pat. No. 3,591,584. These may be converted to the corresponding alkoxycompound by contacting them with a halide, preferably the iodide, of theformula R Z in a reaction inert solvent such as acetone in the presenceof a halide scavenger such as potassium carbonate at reflux temperatureuntil the reaction is substantially complete. Said ester may then behydrolyzed by methods well-known to those skilled in the art to providean alternate source of the novel carboxylic acid intermediates of thepresent invention.

For conversion to carboxamide anti-inflammatory products, said acid isthen dispersed in a suitable reaction-inert solvent such astetrahydrofuran, dioxane, chloroform, methylene chloride or acetonitrileat a concentration of at least 0.2% by weight. Reactioninert solventsare those which are substantially free of adverse effects on reactantsand products under the conditions employed. Said solvent should be driedbefore use. To the reaction medium is then added at least asubstantially equimolar portion of an amine of the formula R Nl-lPreferred amines are Z-thiazolyland 2-pyridylamine. Since the amine isfrequently less expensive than the acid, the addition of an excess ofamine to force the reaction to completion is preferred. Amines do notusually react with acids to give good yields under normal reactionconditions. A number of agents are known especially to those skilled inthe art of peptide chemistry, which promote this reaction. Said agentsare believed to function as dehydrating agents, either causing the acidto form an anhydride or forming an activated mixed anhydride with theacid. Among the agents which promote coupling are N-ethylcarbonyl-Z-ethoxy-l ,Z-dihydroquinoline, dicyclohexylcarbodiimide,N,Ncarbonyldiimidazole and POCl The preferred coupling promoter is saiddihydroquinoline. A portion of said coupling promoter substantiallyequimolar with the amount of acid present is added and the reactionstirred at room temperature until substantially complete. It ispreferred that additional portions of the coupling promoter be addedduring the course of the reaction to increase yields so that a twotofourfold molar excess is added in total. The carboxamide product isrecovered by concentrating the reaction mixture to dryness in vacuo,dissolving the residue in an organic solvent such as one of thepetroleum ethers, separating the insoluble residue by filtration andconcentrating to dryness again. The residue which remains is dissolvedin a minimum amount of a polar, waterimmiscible solvent such asmethylene chloride or chloroform, washed with water and dilute mineralacid and again concentrated to dryness in vacuo. The crude carboxamidemay be used directly in the next synthetic step.

Said crude carboxamide at a concentration of at least 1% by weight isthen dissolved in a reaction-inert medium containing a mineral acid. Thepreferred reactioninert medium is acetic acid containing about 20 to 40%hydrobromic acid by weight. The solution is then heated at a temperatureof about 50 to C. until the formation of a precipitate ceases. Thesolids are collected by filtration, washed with water and air dried toyield a 2,3-dihydro-oxo-2-R -N-R -2H-l ,2-benzothiazine-carboxamide-1,l-dioxide of Formula V or VI.

EXAMPLE I 4-lsopropoxy-2-methyl 2l-l- 1 ,2-Benzothiazine-3- CarboxylicAcid 1, l -Dioxide.

A dark red solution of 300 mg. (1.0 mmole) of 3-acetyl-4-isopropoxy-2methyl-2H-l ,2-benzothiazine l,l-dioxide [Zinnes etal., Journal of Organic Chemistry, Vol. 30, p. 2241 (1965).], 254 mg.(1.0 mmole of iodine and 3 ml. of dry pyridine was heated on a steambath for 7.5 hours. The reaction was then allowed to stand at roomtemperature for 7 days. Concentration of the reaction produced a brownviscous oil, presumably the pyridinium salt, which was used in the nextstep without further purification. A solution of (1.0 mmole) the crudepyridinum salt from the above reaction, 10 ml. of lON potassiumhydroxide and 1 ml. of water was heated at for 1.5 hours. The reactionwas then cooled, diluted with water and acidified with 3N hydrochloricacid. The acidic mixture was extracted3 times with ether and thecombined ether extracts washed with 250 m1. of saturated sodiumbicarbonate. The basic aqueous layer was treated with charcoal, filteredand acidified with 3N hydrochloric acid. ,The aqueous acidic layer wasextracted three times with ether,'dried (sodium sulfate) andconcentrated to an oil which slowly crystallized: 1 10 mg. (37% overallyield for the two steps); m.p. l52l54: i.r.-2.8 (OH) 5.95 (C=O).

Anal. Calcd for C H O NS: Found:

EXAMPLE II The procedure of Example I is followed to produce thefollowing 3-carboxylic acids starting in each case with thecorresponding 3-acetyl compound:

4-Isopropoxy-2-Methy1-N-(2-Thiazolyl)-2H-1,2-Benzothiazine-3-Carboxamide 1 1 -Dioxide.

To a solution of 40 mg. "(0.135 mmole) of 4- isopropoxy-Z-methyl-ZH-l,2-benzothiazine-3- carboxylic acid 1,1-dioxide in 1.5 ml. of drytetrahydrofuran was added 14.2 mg. (0.142 mmole) of 2- aminothiazole in0.5 ml of dry tetrahydrofuran. After addition of 37 mg. (0.15 mmole) ofN-ethoxycarbonyl- 2-ethoxy-l ,2-dihydroquinoline (EEDQ) in 2 ml. dry oftetrahydrofuran, the reaction was stirred for 1 12 hours at roomtemperature with additional 37 mg. portions of EEDQ added at the 16thand 40th hours. Concentration of the reaction to dryness on a rotaryevaporator gave a semi-solid which was slurried in ether and filtered.The ether filtrate was concentrated to dryness, taken up in 20 ml. ofmethylene chloride and washed twice with ml. of 0.5N hydrochloric acidand once with water. The dried methylene chloride layer was concentratedto a dark tan gum; mass spectrum M.+ 379 (calc. 379). This crudematerial was carried on to the next step without further purification.

In similar fashion, the 3-carboxylic acids of Example II may beconverted to the corresponding N-(2- thiazo1yI)-2H-l,2-benzothiazine-3-carboxamide-1-,1-'

dioxides. Y

EXAMPLE IV I 5 -brom'o-2-thiazolyl,

Benzothiazine-3-Carboxamide 1,1-Dioxide.

A solution of 20 mg. (0.053 mmole) of 4-isopropoxy- 2-methyl-N-(2-thiazolyl)-2H-1 ,2-benzothiazine-3- carboxamide 1,1-dioxide and 1.0ml. of 32% hydrobromic acid in acetic acid was stirred at roomtemperature for 0.5 hr. Upon heating the solution to a precipitateformed within 15 minutes. After heating at 90 for 10 minutes thesuspension was cooled, the solids filtered, washed well with water anddried: 4.0 mg. (22%), m.p. 243 dec. Mass spectrum: M.+= 337(superimposable with a mass spectrum of authentic material). Mixturemelting point with authentic material (m.p. 242 dec. Thin layerchromatographic (9:1 acetone-hexane eluent using Brinkman 0.25 m.m.precoated TLC plates, silica gel, 1 -254) comparison of the product withauthentic material confirmed their identity.

r In similar fashion, the 4-alkoxy compounds of Example 111 may beconverted to the corresponding 3,4- dihydro-4-oxo-N-(2thiazo1y1)-2H-1,2-benzothiazine- 3-carboxamide-1,l-dioxides.

EXAMPLE V The procedure of Example III is followed using the compoundsof Examples I and II as starting materials to produce carboxamidespyridyl, 2-pyraziny1, 2-pyrimidyl, 4,5 -dimethyl-2- pyrimidyl,4-pyrimidy1, 5-methyl-3-pyrazinyl, 6- methoxy-3-pyridazinyl,1-pheny1-3-pyrazo1ony1, 2-

thiazolyl, 4-methy1-2-thiazolyl, 4-phenyl-2-thiazolyl,

4,5-dimethyl-2-thiazolyl, f 3- isothiazolyl, 2-benzothiazolyl,6-methyl-2- benzothiazolyl, 4-chloro-2-benzothiazolyl, 6 -bromo-2-benzothiazolyl, 5-chloro-2ebenzoxazolyl, 1,3 ,4- thiadiazolyl,S-methyl-l,2,4-thiadiazolyl, S-methyl- 1,3,4-thiadiazolyl,1,2,4-triazolyl, 1 6 -pheny1-1,2,4- triazolyl, 7-indaz'oly1 and mono--and di-substituted phenyl wherein each substituent is halogen, hydroxy,alkoxy and thioalkoxy having up to 3 carbon atoms, alkyl having up to 4carbon atoms, trifluoromethyl, acetyl, methylsulfinyl andmethylsulfonyl.

' EXAMPLE vi" A 3,4-Dihydro-2-Methyl-3-Oxo+4-Acetyl-2l-I-1 ,2-Benzothiazine- 1 1 -Dioxide.'

by a stream of nitrogen. The solid precipitatewhich.

forms is collected by filtration, dissolved in a minimum amount ofboiling isopropanol, cooled to 0C. and the precipitate collected byfiltration and air dried to yield the title compound.

EXAMPLE VII 3-Isopropoxy-2-Methyl-4-Acetyl-2I-I- l ,2-Benzothiazinel l-Dioxide EXAMPLE VIII 3-Alkoxy-4-Acetyl-2l-I- l ,2-Benzothiazinel l-Dioxides Following the procedure of Examples VI and VII, the followingcompounds may be produced starting-in each case with the appropriate3-oxo-2l-I-l ,Z-benzothiazinel,l-dioxide.

C-NHR using the compounds of Examples VII and VIII as startingmaterials. R is selected from the group consisting of hydrogen, alkylhaving from 1 to 8 carbon atoms, al-

kenyl having up to 6 carbon atoms, cycloalkyl having up to eight carbonatoms, phenylalkyl having up to 3 carbon atoms in the alkyl moiety,phenyl, nitrophenyl, naphthyl, 2-pyridyl, 3-methyl-2-pyridyl,4-methyl-2- 10 pyridyl, '5-methyl-2-pyridyl, 6-methyl-2-pyridyl,4,6-dimethyl-2-pyridyl, 5-chloro-2-pyridyl, 5-bromo-2- pyridyl,5-nitro-2-pyridyl, 5-carboxamido-2-pyridyl, 2-pyrazinyl, Z-pyrimidyl,4,5-dimethyl-2-pyrimidyl, 4- pyrimidyl, 5-methyl-3-pyrazinyl,6-methoxy-3- pyridiazinyl, l-phenyl-S-pyrazolonyl, 2-thiazolyl,4-methyl-2-thiazolyl, 4-phenyl-2-thiazolyl, 5-bromo-2- thiazolyl,4,5-dimethyl-2-thiazolyl, 3-isothiazolyl, 2- benzothiazolyl,6-methyl-2-ben2othiazolyl, 4-chloro-2- benzothiazolyl,6bromo-2-benzothiazolyl, 5-chloro-2- benzoxazolyl, 1 ,3,4-thiadiazolyl,5-methyll ,2,4 thiadiazolyl, S-methyll ,3,4-thiadiazolyl, l ,2,4-triazolyl, 6-phenyl-l.,2,4-triazolyl, 7-indazolyl and mono anddi-substituted phenyl wherein each substituent is halogen,hydroxy,alkoxy-: and thioalkoxy having up to 3 carbon atoms, alkylhavingup to 4 carbon atoms, trifluoromethyl, acetyl, methylsulfinyl andmethylsulfonyl.

What is claimed is: 1. A compound selected from he group consisting ofthose of the formulae F wherein X and Y are each selected from the groupconsisting of hydrogen, fluorine, chlorine, bromine, nitro,tirfluoromethyl and alkyl and alkoxy having up to 5 carbon atoms;

R is selected from the group consisting of hydrogen, alkyl having up to6 carbon atoms, alkenyl having up to 4 carbon atoms and phenyl alkylhaving up to 3 carbon atoms in the alkyl moiety;

and R is selected from the group consisting of lower alkyl, andphenylalkyl having up to 3 carbon atoms in the alkyl moiety.

2. The 3-carboxylic acid of claim 1 wherein X and Y are both hydrogen.

3. The 3-carboxylic acid of claim 1 wherein R is methyl.

4. The 3-carboxylic acid of claim 1 wherein R is isopropyl.

5. 4-Isopropoxy-2-methyl-2l-I-l,2-ben2othiazine-3- carboxylic acid-1 l-dioxide.

6. A process for preparing a compound selected from the group consistingof X 0 O O X ii NHR C-NHR 2 and Y 0 R 0 wherein X and Y are eachselected from the group consisting of hydrogen, fluorine, chlorine,bromine, nitro, trifluoromethyl and alkyl and alkoxy each having up to 5carbon atoms;

R is selected from the group consisting of hydrogen, alkyl having up to6 carbon atoms, alkenyl having up to 4 carbon atoms and phenylalkylhaving up to 3 carbon atoms in the alkyl moiety; i

R is selected from the group consisting of hydrogen, alkyl having up to8 carbon atoms, alkenyl having up to 6 carbon atoms, cycloalkyl havingup to 8 carbon atoms, phenylalkyl having up to 3 carbon atoms in thealkyl moiety, phenyl, nitrophenyl, naphthyl, 2-pyridyl,3-methyl-2-pyridyl, 4-methyl- Z-pyridyl, 5-methyl-2-pyridyl,6-methyl-2-pyridyl,

4,6-dimethyl-2-pyridyl, 5-chloro-2-pyridyl, 5- bromo-2-pyridyl,5-nitro-2-pyridyl 5-carboxamido-Z-pyridyl, Z-pyrazinyl Z-pyrimidyl4,5-dimethyl-2-pyrimidyl, 4-pyrimidyl, 5-methyl-3- pyrazinyl,6-methoxy-3-pyridazinyl, l-phenyl-3- pyrazolonyl, 2-thiazolyl,4-methyl-2-thiazolyl, 4-phenyl-2-thiazolyl, 1 5-bromo-2-thiazolyl,4,5-dimethyl-2-thiazolyl, 3-isothiazolyl, 2-

benzothiazolyl, 6-methyl-2-benzothiazolyl, 4-chloro-2-benzothiazolyl,6-bromo-2- benzothiazolyl, 5-chloro-2-benzoxazolyl, 'l ,3,4-

with a substantially equirnolar portion of an amine of the structure RNH in reaction-inert solvent in the presence of an approximately twotofour-fold molar excess of a coupling promoter selected from the groupconsisting of N-ethoxycarbonyl-2-ethoxy-l ,2- dihydroquinoline,dicyclohexylcarbodiimide, N,N- carbonyldiimidazole and POCL, untilreaction is substantially complete;

and contacting the resulting carboxamide with mineral' acid inreaction-inert solvent at a temperature between about 50 and C, untilreaction is substantially complete. v I t 7.; The process of claim 6wherein R NH is 2- aminothiazole.

8. The process of claim 6 wherein R NH is 2- aminopyridine.

9. The process of claim 6 wherein said coupling promoter isN-ethoxycarbonyl-Z-ethoxy-l ,2- dihydroquinoline. i

10. The process of claim 6 wherein contact with said amine is effectedbetween about- 15 and 50C.

1 l. The process of claim 6 wherein said mineral acid is hydrobromicacid.

12. The process of claim 6 wherein contact with said mineral acid iseffected in acetic acid.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THOSE OF THEFORMULAE
 2. The 3-carboxylic acid of claim 1 wherein X and Y are bothhydrogen.
 3. The 3-carboxylic acid of claim 1 wherein R1 is methyl. 4.The 3-carboxylic acid of claim 1 wherein R3 is isopropyl. 5.4-Isopropoxy-2-methyl-2H-1,2-benzothiazine-3-carboxylicacid-1,1-dioxide.
 6. A process for preparing a compound selected fromthe group consisting of
 7. The process of claim 6 wherein R2NH2 is2-aminothiazole.
 8. The process of claim 6 wherein R2NH2 is2-aminopyridine.
 9. The process of claim 6 wherein said couplingpromoter is N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline.
 10. Theprocess of claim 6 wherein contact with said amine is effected betweenabout 15* and 50*C.
 11. The process of claim 6 wherein said mineral acidis hydrobromic acid.
 12. The process of claim 6 wherein contact withsaid mineral acid is effected in acetic acid.